The impact of genetic risk on liver fibrosis in non‐alcoholic fatty liver disease as assessed by magnetic resonance elastography

Abstract

Background: Variants in multiple genetic loci modify the risk of non-alcoholic fatty liver disease (NAFLD) and cirrhosis but there are limited data on the quantitative impact of variant copies on liver fibrosis. Aim:To investigate the effect of PNPLA3, TM6SF2, MBOAT7, GCKR and HSD17B13 genotype on liver fibrosis assessed by magnetic resonance elastography (MRE), a reproducible, accurate, continuous biomarker of liver fibrosis.Methods: This is a cross-sectional analysis derived from a well-characterised cohort at risk for NAFLD who underwent genotyping and MRE assessment. Liver stiffness (LS) was estimated using MRE and advanced fibrosis was defined as liver stiffness ≥3.63 kilopascals (kPa). Univariable and multivariable linear and logistic regression analysis, were used to assess the association between genotype and MRE.Results: Two hundred sixty-four patients (63% women) with a mean age 53 (±17) years, and 31% Hispanic ethnicity with genotyping and MRE were included. The odds of advanced fibrosis were 3.1 (95% CI: 1.1-8.9, P = 0.04) for CG and 6.5 (95% CI: 2.2-18.9, P < 0.01) for GG compared to CC PNPLA3 genotype. Each PNPLA3 risk variant copy was associated with 0.40 kPa (95% CI: 0.19-0.61, P < 0.01) increase in LS on MRE in analysis adjusted for age, sex and BMI and there was significant genotype-age interaction (P < 0.01). Conversely, the protective TA allele in HSD17B13 was associated with a −0.41 kPa (95% CI: −0.76 to −0.05, P = 0.03) decrease in liver stiffness on MRE multivariable analysis. Conclusion:Knowledge of PNPLA3 and HSD17B13 genotype may assist in the noninvasive risk stratification of NAFLD with closer monitoring recommended for those with high genetic risk. | 69AJMERA Et Al.

Non-invasive diagnosis and staging of non-alcoholic fatty liver disease

“…The primary hepatic effects of the I148M protein variant are most likely attributable to its repression of lipase activity [ 109 ], resulting in increased intracellular accumulation of triglycerides with the number of risk alleles (the G allele). In a recent study in which subjects were phenotyped by MRI-PDFF, each copy of the PNPLA3 risk allele was associated with a 2.56% increase in hepatic steatosis [ 110 ]. In addition, cumulative evidence also suggests that PNPLA3 is associated with fibrosis progression, development of HCC, ESLD, and all-cause mortality [ 111 ].…”

Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease

“…It is important to note that the rs626283 SNP is in strong linkage disequilibrium with rs641738 across numerous studies (23). Although the majority of large studies find a clear association between MBOAT7 loss of function and NAFLD progression, it is important to point out that not all studies have found statistically significant associations (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Although consistent trends in association exist, several independent studies looking at NAFLD-related indices in adults (24)(25)(26)(27)(28)(29)(30)(31) and children (32)(33)(34)(35) have failed to conclude that the rs641738 SNP is associated with NAFLD progression.…”

“…Although the majority of large studies find a clear association between MBOAT7 loss of function and NAFLD progression, it is important to point out that not all studies have found statistically significant associations (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Although consistent trends in association exist, several independent studies looking at NAFLD-related indices in adults (24)(25)(26)(27)(28)(29)(30)(31) and children (32)(33)(34)(35) have failed to conclude that the rs641738 SNP is associated with NAFLD progression. However, it is important to consider that a recent metaanalysis of all published studies including over 1 million subjects confirmed that the rs641738 variant is a risk factor for the presence and severity of NAFLD in individuals of European descent (36).…”

Non-alcoholic fatty liver disease and the impact of genetic, epigenetic and environmental factors in the offspring

“…They concluded that average pre-gestational BMI, breastfeeding for at least six months and avoiding early supplementary formula milk feeding reduce the risk of NAFLD diagnosis by liver ultrasound[ 50 ]. Additionally, more extended maintenance of breastfeeding resulted in multiple benefits on maternal metabolism and a lower risk of NAFLD in mid-life[ 51 - 53 ].…”